1. Toxicology Concepts

2. Risk
The likelihood of injury or disease resulting from exposure to a potential hazard
Evaluation of risk embodies all the basic concepts of toxicology

3. The science of Toxicology helps people make informed decisions and balance RISKS vs. BENEFITS
The study found the highest levels of pesticide residues in peaches, apples, pears…….
AND Spinach.

4. Exposure Sources of exposure to chemicals
Environmental, including home and school
Occupational
Therapeutic
Dietary
Accidental
Deliberate

5. Exposure
In order for a chemical to produce a biological effect, it must first reach a target individual (exposure pathway).
Then the chemical must reach a target site within the body (toxicokinetics).
Toxicity is a function of the effective dose (how much) of a foreign chemical (xenobiotic) at its target site, integrated over time (how long).
Individual factors such as body weight will influence the dose at the target site X =

6. Exposure Route of Exposure
The route (site) of exposure is an important determinant of the ultimate dose—different routes may result in different rates of absorption.
Dermal (skin)
Inhalation (lung)
Oral ingestion (Gastrointestinal)
Injection
The route of exposure may be important if there are tissue-specific toxic responses.
Toxic effects may be local or systemic

7. Exposure Time of Exposure
How long an organism is exposed to a chemical is important
Duration and frequency contribute to dose. Both may alter toxic effects.
Acute Exposure = usually entails a single exposure
Chronic Exposures = multiple exposures over time (frequency)

8. Father of Modern Toxicology Paracelsus—1564
Dose
THE KEY CONCEPT in Toxicology
Father of Modern Toxicology Paracelsus—1564
“All things are poisonous, only the dose makes it non-poisonous.”
Dose alone determines toxicity
All chemicals—synthetic or natural—have the capacity
to be toxic

9. Dose
All Interactions between chemicals and biological systems follow a Dose-Response Relationship

10. Dose Woman Dies after Water-drinking Contest: Water
Intoxication eyed in ‘Hold Your Wee for a Wii’ contest Death
SACRAMENTO, California—A woman who competed in a radio station’s contest to see how much water she could drink without going to the bathroom died of water intoxication, the coroner’s office said Saturday.
Updated: 10:24 p.m. ET Jan 13, 2007

11. Dose-Response Relationship
A key concept in Toxicology is the quantitative relationship between the concentration of a xenobiotic in the body and the magnitude of the biological effect it produces.
The magnitude of the effect of a xenobiotic is usually a function of the amount of xenobiotic to which a person is exposed (i.e., “The Dose Makes the Poison”).
In any given population, there will be a range of sensitivities to a xenobiotic. It is extremely useful to know what is the average sensitivity of a population to a xenobiotic, and what the average dose required to elicit a toxic response will be.

12. Dose
The magnitude of the toxic response is proportional to the concentration (how much) of the chemical at the target site.
The concentration of a chemical at the target site is proportional to the dose.
Four important processes control the amount of a chemical that reaches the target site.
Absorption
Tissue distribution
Metabolism
Excretion

13. Determines Whether a Chemical Will Be Beneficial or Poisonous
Dose
Determines Whether a Chemical Will Be Beneficial or Poisonous
Beneficial Dose Toxic Dose
Aspirin 300 – 1,000 mg 1,000 – 30,000 mg
Vitamin A 5000 units/day 50,000 units/day
Oxygen 20% (Air) 50 – 80% (Air)

14. “The Dose Makes the Poison”
Dose-Response Curves
“The Dose Makes the Poison”
Maximum Response
Maximum Response
1.0
1.0
Rate
Approx.
Linear
Range
0.5
0.5
Threshold
EC50
EC50 20 40 60 80
100
0.1
1.0 10
100
Concentration
Concentration
Arithmetic Scale
Logarithmic Scale

15. Dose-Response Relationship “The Dose Makes the Poison”
Animals Sleeping (%)
Phenobarbital (mg/kg) Log Scale
Animals Killed (%)
ED50
LD50
Effective Dose
Lethal Dose
100 60 80 40 20 10 30 50 1 2 3 5 7

16. Population Dose-Response
Mild
Extreme
Many
Few
Number of Individuals
Response to SAME dose
Sensitive Individuals
Maximal
Effect
Resistant Individuals
Minimal
Majority of Individuals
Average Effect

17. Some chemicals have both therapeutic and toxic effects: Vitamin A
Too low: Blindness, dry skin, increased infections
Too high: Anorexia,
anemia, nose bleeds, muscle and joint pain
Adverse response
Threshold
Dose

18. Organs Respond to Chemicals in Various Ways
Desired Effects
Nutritive
Therapeutic
Blood
Organs
Undesired Effects
Toxic

19. Less Toxic Metabolic Product
Some Chemicals Are Transformed by the Body (Metabolized) to Aid Excretion
Liver and other Organs
Detoxication
Less Toxic Metabolic Product
Kidney
Liver
Lung
Urine
Feces / Bile
Expired Air

20. More Toxic Metabolic Product
Some Chemicals are Partially Converted to Products that are More Toxic than the Parent Substance
Liver and other Organs
Activation
More Toxic Metabolic Product

21. Toxicological Paradigm
Toxicodynamics
Toxicokinetics
What We do to the Chemical
What the Chemical Does to Us
Biologically
Effective
Dose
Early
Biological
Effect
Altered
Structure &
Function
Internal
Dose
Exposure
Disease
Susceptibility and
Modifying Factors
(Genetics and Nutritional Status)
Absorption
Distribution
Metabolism
Excretion
Storage

22. The LIVER is the primary site of metabolism
Biotransformation
Metabolism
major mechanism for terminating the biological activity of chemicals
frequently the single most important determinant of the duration and intensity of the pharmacological response to a chemical
Liver
The LIVER is the primary site of metabolism
Biotransformation occurs in the Liver, kidney, lung, gastrointestinal track, and other organs

23. Pharmacogenetics of Metabolism2 4 6 8 1 5
Response Frequency
Fast Metabolizers
Harmful Side Effects
(# of individuals)
Slow Metabolizers
(elevated plasma levels)
Drug Concentration (g/mL)
Plasma levels 6 hrs after oral dose

24. Identify people with different chemical/drug sensitivity
Typical Population
The emerging field of “Pharmacogenomics” or “Toxicogenomics” offers the potential to identify and protect subsets of people predisposed to toxicity from chemicals or drugs
Identify people with different chemical/drug sensitivity
Less Sensitive
Identify People with “normal” responses
More Sensitive

25. Tools of Modern Molecular Toxicology: Genomics and Proteomics
NH2
-COOH R K